期刊
CANCER DISCOVERY
卷 12, 期 2, 页码 468-483出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-21-1376
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资金
- NIH [R01 CA237208, R21 NS114873, R21 CA256575, R33 CA236681]
- Cancer Center Support Grant [P30 CA034196, R01 HG009900, CCF 1955712]
- Department of Defense [W81XWH1910246]
- Musella Foundation
- B*CURED Foundation
- Brain Tumour Charity
- American Brain Tumor Association [BRF1800014]
- American Cancer Society Fellowship [130984-PF-17-141-01-DMC]
- U.S. Department of Defense (DOD) [W81XWH1910246] Funding Source: U.S. Department of Defense (DOD)
Oncogenic ecDNA plays a crucial role in tumor evolution, but our understanding of its biology is limited. In this study, we investigated the distribution and frequency of ecDNA copy number in patient tissues and cell line models. We discovered uneven segregation of ecDNA during mitosis and the formation of ecDNA hubs that drive oncogene transcription.
Oncogenic extrachromosomal DNA elements (ecDNA) play an important role in tumor evolution, but our understanding of ecDNA biology is limited. We determined the distribution of single-cell ecDNA copy number across patient tissues and cell line models and observed how cell-to-cell ecDNA frequency varies greatly . The exceptional intratumoral heterogeneity of ecDNA suggested ecDNA-specifi c replication and propagation mechanisms. To evaluate the transfer of ecDNA genetic material from parental to offspring cells during mitosis, we established the CRISPRbased ecTag method. ecTag leverages ecDNA-specifi c breakpoint sequences to tag ecDNA with fluorescent markers in living cells. Applying ecTag during mitosis revealed disjointed ecDNA inheritance patterns, enabling rapid ecDNA accumulation in individual cells. After mitosis, ecDNAs clustered into ecDNA hubs, and ecDNA hubs colocalized with RNA polymerase II, promoting transcription of cargo oncogenes. Our observations provide direct evidence for uneven segregation of ecDNA and shed new light on mechanisms through which ecDNAs contribute to oncogenesis. SIGNIFICANCE: ecDNAs are vehicles for oncogene amplification. The circular nature of ecDNA affords unique properties, such as mobility and ecDNA-specific replication and segregation behavior. We uncovered fundamental ecDNA properties by tracking ecDNAs in live cells, highlighting uneven and random segregation and ecDNA hubs that drive cargo gene transcription.
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